Time-Restricted Eating and Metformin in Invasive Breast Cancer or DCIS: A Randomized, Phase IIb, Presurgical Trial. Preliminary Safety Analysis.

UNLABELLED: Cancer cells exhibit metabolic flexibility between anaerobic glycolysis and oxidative phosphorylation. Preclinical data showed that metformin, an oxidative phosphorylation inhibitor, combined with fasting-induced hypoglycemia led to activation of the PP2A-GSK3ß-Mcl1 axis and inhibition of tumor growth. A window-of-opportunity trial was designed to evaluate the effect of metformin and nightly fasting on proliferation in invasive breast cancer or ductal carcinoma in situ (DCIS). The primary endpoint is the pretreatment/posttreatment change of Ki67 in cancer tissue, and the co-primary endpoint is the difference in posttreatment Ki67 in cancer-adjacent DCIS or high-risk lesions. Participants with hormone receptor-positive invasive breast cancer or DCIS candidates to surgery are being accrued and randomized to either (i) fasting for ≥16 hours nightly, plus nutritional counseling and daily metformin with continuous glucose monitoring, or (ii) continuous glucose monitoring. The intervention lasts 4 to 6 weeks with gradual metformin ramp up to limit gastrointestinal disturbances. The safety of the combination was evaluated as a primary interim endpoint. The frequency of dose-limiting toxicity (≥G3 adverse events related to treatment) was assessed in the first 14 participants in the experimental arm. Most adverse events were of low grade (G1: 50; 90.9%) and unrelated to the treatment (G1: 26 unrelated; 52%). No one discontinued treatment because of toxicity, and no dose-limiting toxicities were observed, so the escalation phase of metformin was significantly shortened from 7 to 3 days. The results of this project will expand knowledge of this prevention approach and possibly provide the basis for large-scale primary prevention studies in at-risk women.

PREVENTION RELEVANCE: In a context of rising cancer drug costs, this research explores a low-cost treatment to optimize breast cancer preventive intervention. The approach is safe and based on repurposed drugs that could enhance prevention strategies for obesity- and insulin-related cancers, offering immediate applicability to a large-scale trial in women at risk.